The CNS represents the largest part of the nervous system, including the brain and the spinal cord. Traumatic injury to the brain and spinal cord affect 1.4 million and between 10-12 thousand people, respectively, every year in the United States (U.S.). Direct medical costs and indirect costs such as loss of productivity associated with these injuries to the CNS costs billions of dollars annually in the U.S.
A TBI is defined as a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain. The severity of such an injury may range from a brief change in mental status or consciousness to an extended period of unconsciousness or amnesia after the injury. TBI triggers a complex sequence of inflammatory responses that contribute to secondary injury, and has been defined as a predominantly immunological and inflammatory disorder. The endogenous neuroinflammatory response in the injured brain contributes to the breakdown of the blood-brain barrier, and to the development of posttraumatic cerebral edema, neuronal cell death, and to neuropathological sequalae which are, in large part, responsible for the adverse outcome.
Currently, no proven neuroprotective treatments for TBI exist. Although steroids, barbiturates and mild hypothermia have been reported to benefit some TBI patients, these treatments have failed in multi-center trials.
SCI is associated with physical and psychological disorder that causes disability and requires intensive treatment. In SCI, the initial physical trauma to the spinal cord sets off a cascade of biochemical and cellular events that kills neurons, strips axons of their myelin insulation, and triggers an inflammatory immune system response. Neurons continue to die for hours after SCI, and this secondary cell death is mediated by an immune response that activates and processes proinflammatory cytokines Interleukin-10 (IL-1β) and Interleukin-18 (IL-18). Another consequence of the immune system's entry into the CNS is that inflammation accelerates the production of highly reactive forms of oxygen molecules called free radicals. Free radicals are produced as a by-product of normal cell metabolism. In the healthy spinal cord their numbers are small enough that they cause no harm. But injury to the spinal cord, and the subsequent wave of inflammation that sweeps through spinal cord tissue, signals particular cells to overproduce free radicals. Free radicals then attack and disable molecules that are crucial for cell function (e.g., those found in cell membranes) by modifying their chemical structure. Free radicals can also change how cells respond to natural growth and survival factors, and turn these protective factors into agents of destruction.
Methylprednisolone, a steroid drug, is the standard treatment for acute SCI. Methylprednisolone appears to reduce the damage to nerve cells and decreases inflammation near the injury site by suppressing activities of immune cells. Methylprednisolone is effective only if used in high doses within eight hours of acute injury, however, high doses of methylprednisolone can lead to side effects, such as infections, and adverse effects on tissue recovery. Indeed, many clinicians feel that the adverse effects of methylprednisolone treatment outweigh the benefits. Thus, methylprednisolone is not routinely given to SCI patients in most large centers.
In traumatic injuries to the CNS, studies suggest that modulation of post-traumatic inflammation may provide the best opportunity to arrest the secondary injury cascade. At present, there are no pharmacologic strategies of proven benefit. Most of the neuroprotective agents are free radical scavengers and many inhibit only one or two aspects of inflammation. Few drugs are found to be effective at modulating inflammation in the CNS after traumatic injury, and their therapeutic benefit is hampered by side effects. Although steroids, for example, continue to be given to patients with SCI in many institutions, evidence of deleterious effects continues to accumulate.
In addition to TBI and SCI, ischemic stroke is an event in which inflammation plays a significant role in the pathology of the disease. More than 750,000 Americans have a stroke each year, making stroke the third leading cause of death in the U.S. Ischemic events initiated by thromboembolic processes such as stroke activate complex pathophysiological mechanisms that result in neurological deficits and neuronal cell death. The initial vascular responses to embolic events also lead to secondary injury mechanisms including inflammation that contributes to the damaging cellular and molecular responses of ischemic injury, e.g., the death of nerve cells. Currently, there are no neuroprotective drugs that have been approved for use in ischemic stroke patients.
The failure of currently available anti-inflammatory agents in offering significant neuroprotection in large epidemiologic clinical trials of CNS disorders suggests an urgent need for the development of new neuroprotective agents.